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WO2009117597A1 - Modulation de la réponse immunitaire - Google Patents

Modulation de la réponse immunitaire Download PDF

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Publication number
WO2009117597A1
WO2009117597A1 PCT/US2009/037696 US2009037696W WO2009117597A1 WO 2009117597 A1 WO2009117597 A1 WO 2009117597A1 US 2009037696 W US2009037696 W US 2009037696W WO 2009117597 A1 WO2009117597 A1 WO 2009117597A1
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Prior art keywords
cells
ficz
subject
ahr
cell
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Inventor
Howard Weiner
Francisco J. Quintana
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Brigham and Womens Hospital Inc
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Brigham and Womens Hospital Inc
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Priority claimed from PCT/US2008/083016 external-priority patent/WO2009067349A2/fr
Application filed by Brigham and Womens Hospital Inc filed Critical Brigham and Womens Hospital Inc
Priority to US12/933,800 priority Critical patent/US20110262457A1/en
Priority to EP09721374A priority patent/EP2276833A4/fr
Priority to AU2009225541A priority patent/AU2009225541A1/en
Priority to CA2755933A priority patent/CA2755933A1/fr
Priority to JP2011500961A priority patent/JP2011519266A/ja
Publication of WO2009117597A1 publication Critical patent/WO2009117597A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/10—Growth factors
    • C12N2501/15—Transforming growth factor beta (TGF-β)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/20—Cytokines; Chemokines
    • C12N2501/23—Interleukins [IL]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/30—Hormones
    • C12N2501/38—Hormones with nuclear receptors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/60—Transcription factors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/999—Small molecules not provided for elsewhere

Definitions

  • This invention relates to methods and compositions for enhancing a subject's immune response by increasing the number and/or activity of IL-17-producing T cells (T H 17)) in vivo and in vitro.
  • Treg BACKGROUND Regulatory T cells
  • TGF ⁇ l induces the differentiation of Treg (Chen et ah, J. Exp. Med., 198: 1875- 1886, 2003).
  • TGF ⁇ l in combination with IL-6 (Veldhoen et ah, Immunity, 24: 179-189, 2006) or IL-21 (Korn et al, Nature, 448:484-7, 2007) results in the differentiation of T H 17 cells.
  • Treg and T H 17 play in the immune response to pathogens, characterization of the pathways involved and identification of compounds capable of modulating these pathways, e.g., to promote the generation (e.g., differentiation of cells to or towards) of T H 17 cells or to promote increased activity of T H 17 cells is important for the treatment of, e.g., infections and cancer.
  • the present invention is based, at least in part, on the discovery that compounds capable of modulating (e.g., increasing or decreasing) the expression and/or activity of the Aryl Hydrocarbon Receptor (AHR) provide useful targets for enhancing the immune response.
  • AITR activation by 2,3.7,8-tetrac1i3orodibcnzo-p- dioxin (TCDD) induced ' I teg cells that suppressed experimental autoimmune encephalomyelitis (t ⁇ t) by a TGt -bl -dependent mechanism
  • AHR activation by 6-formylindoio[3.2-b]carbazoie (FlCZ) or beta-naphthoflavone (bNF) interfered with Tr ⁇ g cell differentiation, boosted Tn!
  • the present invention provides, inter alia, compositions and methods for the prevention or treatment of diseases caused by a deficient (e.g., absent or insufficient) immune response.
  • the invention features methods for increasing the number or activity of T cells producing IL- 17 (T H 17) in a population of T cells.
  • the methods include contacting the population of cells with a sufficient amount of a composition comprising an AHR ligand that reduces expression of Foxp3, e.g., 6- formylindolo[3,2-b]carbazole (FICZ) or beta-naphthoflavone (bNF), optionally linked to a biocompatible nanoparticle, and optionally evaluating the presence and/or number of IL-17-expressing cells in the population.
  • the methods result in an increase in the number and/or activity of T H 17 cells.
  • the initial population of T cells includes one or both of na ⁇ ve T cells or CD4 + CD62 ligand + T cells.
  • the population of T cells can be isolated, i.e., in vitro, or in a living mammalian subject, e.g., a subject who has a tumor, an infection, or is immunosuppressed.
  • the population of cells can also be administered as an adjuvant, e.g., in young children or the elderly, to boost the immune response to a vaccine.
  • the present methods can be used in subjects who are immunosuppressed as a result of infection with human immunodeficiency virus (HIV), a condition that is often associated with a deficit of T H 17 cells.
  • the methods can include administering the one or more ligands orally, mucosally, or intravenously.
  • T H 17 cells generated or activated using a method described herein are administered to a subject who is suffering from a tumor or an infection, or who is immunosuppressed, in an amount sufficient to improve or ameliorate a symptom of the disorder.
  • the methods include providing a cell expressing a reporter construct comprising a binding sequence for the Aryl
  • Hyrocarbon Receptor in a mammalian Foxp3 promoter sequence, wherein said binding sequence is operably linked to a reporter gene, for example a reporter gene selected from the group consisting of luciferase, green fluorescent protein, and variants thereof; contacting the cell with a test compound; and evaluating an effect of the test compound on expression of the reporter gene.
  • a test compound that increases or decreases expression of the reporter gene is a candidate compound that modulates generation of T H I 7 cells.
  • the methods can optionally include measuring expression of the reporter construct in the presence of an AHR ligand that reduces expression of Foxp3, e.g., FICZ or bNF; determining whether the candidate compound competes for binding to the AHR with the known compound; and selecting the candidate compound if it binds the AHR competitively with the known compound.
  • an AHR ligand that reduces expression of Foxp3, e.g., FICZ or bNF e.g., FICZ or bNF
  • the present invention provides methods of identifying candidate compounds that modulate the generation of T cells producing IL-17 (T H 17). These methods include providing a cell expressing a reporter construct containing a binding sequence for AHR operably linked to a reporter gene. The cell is then contacted with a test compound, and the effect of the test compound on expression of the reporter gene is evaluated. A test compound that increases or decreases expression of the reporter gene is a candidate compound that modulates generation of T n 17 cells.
  • the present invention provides methods of identifying candidate compounds that modulate generation of T H 17 cells. These methods include providing a living zebrafish, e.g., a zebrafish embryo, e.g., 30 minutes after the egg is laid; contacting the zebrafish with a test compound, e.g., by putting the test compound in water in which the zebrafish is living or micro injecting the compound into an embryo; and evaluating an effect of the test compound on Foxp3 expression in the zebrafish, wherein a test compound that increases or decreases expression of Fox- 3 in the zebrafish is a candidate compound that modulates generation of TH 17 cells.
  • a living zebrafish e.g., a zebrafish embryo, e.g., 30 minutes after the egg is laid
  • a test compound e.g., by putting the test compound in water in which the zebrafish is living or micro injecting the compound into an embryo
  • the present invention provides methods for increasing the numbers of TH 17 cells in a population of T cells. These methods include contacting the cell with one or more AHR ligands that reduce expression of Foxp3, e.g., 6-formylindolo[3,2-b]carbazole (FICZ) or beta-naphthoflavone (bNF), wherein the method results in an increase in the number and/or activity of regulatory IL- 17- producing T cells (TH 17).
  • FICZ 6-formylindolo[3,2-b]carbazole
  • bNF beta-naphthoflavone
  • the present invention provides methods for increasing the numbers of T H 17 cells in a subject.
  • these methods include administering one or more AHR ligands to a subject selected for treatment, e.g., 6-formylindolo[3,2- b]carbazole (FICZ) or beta-naphthoflavone (bNF), wherein the method results in an increase in the number and/or activity of IL- 17-producing T cells (TH 17).
  • a subject selected for treatment e.g., 6-formylindolo[3,2- b]carbazole (FICZ) or beta-naphthoflavone (bNF)
  • FICZ 6-formylindolo[3,2- b]carbazole
  • bNF beta-naphthoflavone
  • the invention provides methods for preparing an enriched population of T cells producing IL-17 (THI 7) from an initial population of T cells.
  • the methods include providing an initial population of T cells; contacting the population of cells with a sufficient amount of a composition comprising an AHR ligand, e.g., 6-formylindolo[3,2-b]carbazole (FICZ) or beta-naphthoflavone (bNF), and optionally evaluating the presence and/or number of T H 17 cells in the population.
  • AHR ligand e.g., 6-formylindolo[3,2-b]carbazole (FICZ) or beta-naphthoflavone (bNF)
  • the initial population of T cells includes na ⁇ ve T cells and/or CD4 + CD62 ligand + T cells.
  • the population of T cells is in vitro, and the methods further include contacting the cells with an effective amount of one or both of interleukin-6 (IL-6) and transforming growth factor (TGF)-beta.
  • the methods further include contacting the cells with one or more antibodies that selectively bind to an antigen present on a T cell, a B cell, a dendritic cell, or a macrophage.
  • the antibody is linked to a biocompatible nanoparticle. In embodiments where both the antibody and the AHR ligand are linked to nanoparticles, they can be present on the same nanoparticles or on separate nanoparticles.
  • the methods further include preparing the enriched population for administration to a subject. In some embodiments, the methods further include administering the T H 17 cells to a subject suffering from a disorder that would benefit from an enhanced T ⁇ lV-mediated immune response, in an amount sufficient to improve or ameliorate a symptom of the disorder.
  • the invention features methods for treating a subject having a disease that would benefit from an enhanced TeH-mediated immune response, e.g., a tumor or an infection with a pathogen, e.g., a virus, fungus, bacterium, or protozoa.
  • the methods include identifying a subject in need of treatment that would increase an immune response, e.g., selecting a subject on the basis that they have a disease that would benefit from increased immune response; and administering to the subject a composition comprising a therapeutically effective amount of an AHR ligand, e.g., 6- formylindolo[3,2-b]carbazole (FICZ) or beta-naphthoflavone (bNF), thereby treating the subject.
  • an AHR ligand e.g., 6- formylindolo[3,2-b]carbazole (FICZ) or beta-naphthoflavone (bNF
  • the subject is infected with a pathogen selected from the group consisting of viruses, bacteria, fungi, and protozoa. In some embodiments, the subject has cancer.
  • the FICZ or bNF is linked to a biocompatible nanoparticle.
  • the methods further include administering to the subject one or more antibodies that selectively bind to an antigen present on a T cell, a B cell, a dendritic cell, or a macrophage.
  • the antibody is linked to a biocompatible nanoparticle. In embodiments where both the antibody and the AHR ligand are linked to nanoparticles, they can be present on the same nanoparticles or on separate nanoparticles.
  • the methods include administering an antigen associated with the disease in the subject, e.g., a tumor-associated antigen or an antigen that is associated with a pathogen selected from the group consisting of viruses, bacteria, fungi, and protozoa, depending on which pathogen the subject is infected with.
  • an antigen associated with the disease in the subject e.g., a tumor-associated antigen or an antigen that is associated with a pathogen selected from the group consisting of viruses, bacteria, fungi, and protozoa, depending on which pathogen the subject is infected with.
  • the present invention features compositions including a ligand that binds specifically to an aryl hydrocarbon receptor (AHR) transcription and that reduces expression of Foxp3, e.g., linked to a biocompatible nanoparticle.
  • the ligand can be, e.g., 6-formylindolo[3,2-b]carbazole (FICZ) or beta-naphthoflavone (bNF).
  • the composition also includes an antibody that selectively binds to an antigen present on a T cell, a B cell, a dendritic cell, or a macrophage.
  • the antibody can be present on (i.e., linked to) the same nanoparticles, linked to different nanoparticles (of the same or different types) or free in solution.
  • the composition also includes an inhibitor of degradation of the ligand, e.g., a monoamine oxidase inhibitor such as tranylcypromine.
  • the inhibitor can be present on (i.e., linked to) the same nanoparticles, linked to different nanoparticles (of the same or different types) or free in solution.
  • the methods and compositions described herein include the use of a ligand that binds specifically to an aryl hydrocarbon receptor (AHR) transcription factor and reduces expression of Foxp3, e.g.,, and an inhibitor of degradation thereof, wherein both, one, or neither is linked to a nanoparticle.
  • AHR aryl hydrocarbon receptor
  • treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered.
  • amelioration of the symptoms of a particular disorder refers to any lessening, whether permanent or temporary, lasting or transient of the symptoms, that can be attributed to or associated with treatment by the compositions and methods of the present invention.
  • an effective amount and “effective to treat,” as used herein, refer to an amount or a concentration of one or more of the compositions described herein utilized for a period of time (including acute or chronic administration and periodic or continuous administration) that is effective within the context of its administration for causing an intended effect or physiological outcome.
  • subject is used throughout the specification to describe an animal, human or non-human, rodent or non-rodent, to whom treatment according to the methods of the present invention is provided.
  • Veterinary and non-veterinary applications are contemplated.
  • the term includes, but is not limited to, mammals, e.g., humans, other primates, pigs, rodents such as mice and rats, rabbits, guinea pigs, hamsters, cows, horses, cats, dogs, sheep and goats. Typical subjects include humans, farm animals, and domestic pets such as cats and dogs.
  • gene as used herein refers to an isolated or purified gene.
  • isolated or purified when applied to a nucleic acid molecule or gene, includes nucleic acid molecules that are separated from other materials, including other nucleic acids, which are present in the natural source of the nucleic acid molecule.
  • An "isolated" nucleic acid molecule such as an mRNA or cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized.
  • an “isolated” or “purified” polypeptide, peptide, or protein is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized.
  • substantially free means that the preparation of a selected protein has less than about 30%, (e.g., less than 20%, 10%, or 5%) by dry weight, of non-selected protein or of chemical precursors. Such a non- selected protein is also referred to herein as "contaminating protein”.
  • the isolated therapeutic proteins, peptides, or polypeptides When the isolated therapeutic proteins, peptides, or polypeptides are recombinantly produced, it can be substantially free of culture medium, i.e., culture medium represents less than about 20%, (e.g., less than about 10% or 5%) of the volume of the protein preparation.
  • culture medium represents less than about 20%, (e.g., less than about 10% or 5%) of the volume of the protein preparation.
  • the invention includes isolated or purified preparations of at least 0.01, 0.1, 1.0, and 10 milligrams in dry weight. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting.
  • FIGs. IA- II show that treatment of T cells with AHR ligands induced differentiation into either Treg or T H 17, depending on the ligand used.
  • Fig. IA is a set of three FACS plots showing conversion of CD4 Foxp3:GFP ⁇ T cells into CD4 + Foxp3:GFP + Treg by stimulation with antibodies to CD3 and CD28 in the presence of TGFbI with or without FICZ; Fig Ib; Fig. IB presents the data in bar graph format.
  • FIG. 1C is a bar graph showing AHR expression in na ⁇ ve T cells differentiated in vitro into T H 1, T H 2 or T H 17 cells for four days (mean + s.d. of triplicates normalized to actin expression).
  • FIG. 1C is a bar graph showing AHR expression in na ⁇ ve T cells differentiated in vitro into T H 1, T H 2 or T H 17 cells for four days (mean + s.d. of triplicates normalized to actin expression).
  • FIG. ID is a bar graph showing AHR expression in na ⁇ ve T cells differentiated in vitro into T H 17 for four days with the indicated cytokines (mean + s.d. of triplicates normalized to actin expression).
  • FIG. IE is a bar graph showing ROR ⁇ t expression in na ⁇ ve T cells differentiated into TH 17 for four days with TGF ⁇ l and IL-6 alone or in combination with FICZ (mean + s.d. of triplicates normalized to actin expression).
  • FIG. IF is a set of nine FACS plots of frequency of IL-17 + T cells differentiated with TGF ⁇ l and IL-6 alone or in combination with IL-23 and/or FICZ for four days.
  • FIG. 2A is a line graph showing development of EAE on FICZ " or control- treated mice (mean EAE score + s.e.m.)
  • FIG. 2B is a pair of bar graphs showing cytokine secretion (pg/ml) triggered by MOG 35 _ 55 in splenocytes taken from FICZ or control-treated mice; left, IFNgamma, right, IL- 17.
  • FIGs. 2C-2E are each pairs of FACS plots showing the frequency of IFN ⁇ , (2C), IL- 17 (2D) or Foxp3 (2E) in splenocytes from FICZ or control-treated mice.
  • FIGs. 3 A and 3B are bar graphs illustrating AFP levels in HCC tumor models treated with FICZ (3A) or FICZ plus HBSAg (3B).
  • FIGs. 4A-4C are bar graphs showing changes in levels of CD3 (4A),
  • FIG. 4D is a bar graph showing the effect of a specific morpholino antisense oligonucleotide against Foxp3 on IL- 17 expression in zebrafish.
  • FIG. 5 is a schematic illustration of gold nanoparticles for AHR-ligand delivery.
  • FIGs. 6A and 6B show the functionality of gold nanoparticles containing
  • AHR-ligands 6A is a bar graph showing activation of luciferase activity in an AHR reporter cell line by nanoparticles linked to AHR ligands TCDD and FICZ. 6B is the absorption spectra of the nanoparticles constructed.
  • FIG. 8 is a bar graph showing fluorescence in 293 cells transfected with an AHR reporter luciferase construct and a TK-Renilla Luciferase construct for normalization purposes. The cells were incubated with different concentrations of the AHR ligand TCDD and activation of the AHR reporter was followed by monitoring fluorescence from the luciferase.
  • FIG. 9 is a bar graph T cells differentiation into Th 17 cells by in vitro activation with antibodies to CD3 and CD28 in the presence of TGF -beta and IL-21, in the presence of or not of showing beta-naphthoflavone (bNF) or FICZ (100 nM). IL- 17 production was measured by real time PCR.
  • bNF beta-naphthoflavone
  • FICZ 100 nM
  • T H 17 T H 17
  • characterization of the pathways and identification of compounds capable of modulating these pathways e.g., to promote the generation (e.g., differentiation of cells to or towards) T H 17 cells or that promote increased activity of T H 17 cells is important for the treatment of, e.g., infections and cancer.
  • the present invention provides, inter alia, compositions and methods useful for therapeutic immunomodulation.
  • the present invention is based, at least in part, on the discovery that modulation of the AhR by certain high-affinity ligands as described herein can be used to modulate (e.g., increase or decrease the number and/or activity of) T H 17 cells in vitro and in vivo.
  • other AHR-specific ligands such as T also regulate differentiation of regulatory T cells (Treg) (see PCT International Patent Application NO. PCT/US2008/083016, and U.S. Provisional Patent Application Serial No. 60/989,309, filed on November 20, 2007, both of which are incorporated herein by reference in their entirety), making the AHR a useful target for immune-based therapies.
  • the data presented herein demonstrates the use of AHR-specific ligands that reduce expression of Foxp3, e.g., 6-formylindolo[3,2-b]carbazole (FICZ) or beta-naphthoflavone (bNF), to promote an increase in the number and/or activity of T cells producing IL- 17 (TH 17), which will be useful to suppress the immune response in the treatment of diseases or disorders associated with an abnormally low immune response, or disorders that would benefit from an enhanced immune response, e.g., infections or cancer.
  • effective doses of the ligand e.g., FICZ or bNF
  • the data presented herein demonstrates the use of AHR ligands that reduce expression of Foxp3, e.g.,6-formylindolo[3,2-b]carbazole (FICZ) or beta- naphthoflavone (bNF), to promote an increase in the number and/or activity of TH 17 immunomodulatory cells, which will be useful to enhance or promote the immune response in the treatment of diseases or disorders caused by an absent or insufficient immune response (e.g., cancer and infection).
  • FICOZ 6-formylindolo[3,2-b]carbazole
  • bNF beta- naphthoflavone
  • Other compounds that act on the AHR as FICZ or bNF does can also be used; a number of other compounds that bind to the AHR are known, and simple assays can be used to determine whether they also increase generation and/or activity of THI 7 cells.
  • a composition including an AHR ligand that reduces expression of Foxp3, e.g., 6-formylindolo[3,2- b]carbazole (FICZ) or beta-naphthoflavone (bNF), is administered to a subject in vivo or to a population of cells in vitro.
  • the ligand is linked to a biocompatible nanoparticle.
  • the composition also includes an antibody that selectively binds to an antigen present on a T cell, a B cell, a dendritic cell, or a macrophage.
  • the antibody can be present on (i.e., linked to) the same nanoparticles, linked to different nanoparticles (of the same or different types) or free in solution.
  • the composition also includes a specific antigen, to induce an antigen-specific response.
  • the antigen can be, e.g., a tumor- or pathogen-specific antigen.
  • Exemplary human AHR mRNA sequences are known in the art and include Genbank Ace. No. NM_001621.3; the amino acid sequence of the protein is Genbank Ace. No. NP_001612.1.
  • Active fragments of AHR are DNA binding fragments with transcription activity, and contain at least one PAS region, e.g., amino acids 122-224 or 282-381 of NP 001612.1.
  • Consensus recognition sequences that bind AHR include the sequence TNGCGTG.
  • the assays include the use of nucleic acids or polypeptides that are at least 80% identical to a human AHR sequence, e.g., at least 80%, 85%, 90%, or 95% identical to a human sequence as described herein.
  • the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and nonhomologous sequences can be disregarded for comparison purposes).
  • the length of a reference sequence aligned for comparison purposes is at least 60%, e.g., at least 70%, 80%, 90%, 100% of the length of the reference sequence.
  • the amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position.
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. MoI. Biol. 48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available on the world wide web at gcg.com), using a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.
  • Test compounds for use in the methods described herein are not limited and can include crude or partially or substantially purified extracts of organic sources, e.g., botanical (e.g., herbal) and algal extracts, inorganic elements or compounds, as well as partially or substantially purified or synthetic compounds, e.g., small molecules, polypeptides, antibodies, and polynucleotides, and libraries thereof.
  • organic sources e.g., botanical (e.g., herbal) and algal extracts, inorganic elements or compounds
  • partially or substantially purified or synthetic compounds e.g., small molecules, polypeptides, antibodies, and polynucleotides, and libraries thereof.
  • a test compound that has been screened by a method described herein and determined to increase levels and/or activity of T H 17 cells herein can be considered a candidate compound for the treatment of a disorder that would benefit from an enhanced immune response, e.g., cancer or an infection.
  • a candidate compound that has been screened, e.g., in an in vivo model of such a disorder, e.g., cancer or an infection, and determined to have a desirable effect on the disorder, e.g., on one or more symptoms of the disorder can be considered a candidate therapeutic agent.
  • Candidate therapeutic agents once screened and verified in a clinical setting, are therapeutic agents.
  • Candidate therapeutic agents and therapeutic agents can be optionally optimized and/or derivatized, and formulated with physiologically acceptable excipients to form pharmaceutical compositions.
  • test compounds are known to bind the AHR.
  • AHR transcription factor ligands are described in Denison and Nagy, Ann. Rev. Pharmacol. Toxicol., 43:309-34, 2003, and references cited herein, all of which are incorporated herein in their entirety.
  • Other such molecules include planar, hydrophobic HAHs (such as the polyhalogenated dibenzo-pdioxins, dibenzofurans, and biphenyls) and PAHs (such as 3-methylcholanthrene, benzo(a)pyrene, benzanthracenes, and benzoflavones), and related compounds. (Denison and Nagy, 2003, supra). Nagy et al., Toxicol. Sci.
  • those ligands useful in the present invention are those that bind competitively with FICZ or bNF.
  • a compound that is useful in the methods described herein binds to the AHR, e.g., competes for binding of the AHR with FICZ or bNF, and thereby increases generation and/or activity of T H 17 cells.
  • suitable compounds will also result in an increase in levels of ROR ⁇ t, a transcription factor associated with differentiation of T H 17 cells.
  • suitable compounds will also result in an increase in levels of IL- 17.
  • mRNA levels are well known in the art and include, but are not limited to, Northern analysis, ribonuclease protection assay, reverse transcription-polymerase chain reaction (RT-PCR), real time PCR, and RNA in situ hybridization (see, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 3 rd Ed., Cold Spring Harbor Laboratory Press (2001)).
  • Transcription factor activity e.g., altered promoter binding and/or transcription activity, can be determined by, e.g., electrophoretic mobility shift assay, DNA footprinting, reporter gene assay, or a serine, threonine, or tyrosine phosphorylation assay.
  • the effect of a test compound on expression, level or activity is observed as a change in glucose tolerance or insulin secretion of the cell, cell extract, co-culture, explant, or subject.
  • the effect of a test compound on expression, level, or activity of a transcription factor is evaluated in a transgenic cell or non-human animal, or explant, tissue, or cell derived therefrom, having altered glucose tolerance or insulin secretion, and can be compared to a control, e.g., wild-type animal, or explant or cell derived therefrom.
  • the ability of a test compound to increase generation and/or activity of T H 17 cells is further evaluated in an animal, e.g., an experimental animal.
  • a compound identified by an in vitro method described herein is administered to an animal for validation.
  • Levels of TH 17 cells can be determined using known methods.
  • levels of IL- 17, IL- 21, or IL-22 can also be evaluated, e.g., using ELISA, ELISPOT, or RT-PCR assays as known in the art (see, e.g., O'Quinn and Palmer, Adv. Immunol, 99: 1 15-163 (2008)).
  • T H l7-derived cytokines e.g., IL-17, IL-21 (Spolski and Leonard, Curr. Op. Immunol. 20:295-301 (2008)), or IL-22, is a useful compound.
  • the present invention is based, at least in part, on the identification of certain AHR ligands as compounds that increase levels and/or activity of TH 17 cells. Accordingly, the present invention provides compositions and methods for treating a subject (e.g., a human) with a condition that would benefit from an enhanced immune response e.g., a condition caused or associated with an absent or insufficient T H 17-mediated immune response.
  • a subject e.g., a human
  • an enhanced immune response e.g., a condition caused or associated with an absent or insufficient T H 17-mediated immune response.
  • the methods can include selecting a subject in need of treatment (e.g., selecting the subject on the basis that they have one or more conditions that would benefit from an enhanced T H 17-mediated immune response) and administering to the subject one or more of the compositions described herein that include as a therapeutic (active) agent an AHR ligand that increases levels or activity of T H 17 cells.
  • a subject in need of treatment can be identified, e.g., by their medical practitioner.
  • Absent or insufficient immune responses may be caused, e.g., by a disease that affects the immune system (e.g., HIV and cancer), by evasion of the host immune response by the invading pathogen, or by tolerance to the immune response.
  • Diseases caused by or resulting from an absent or insufficient immune response that may benefit from treatment using the compositions and methods described herein include, but are not limited to, infection (e.g., bacterial (e.g., Klebsiella pneumonia), viral, fungal (e.g., Candida albicans), and protozoal infections).
  • infection e.g., bacterial (e.g., Klebsiella pneumonia), viral, fungal (e.g., Candida albicans), and protozoal infections.
  • a number of infections known to trigger a TeH-mediated immune response are known in the art, see, e.g., O'Quinn and Palmer, Adv. Immunol, 99: 115-163 (2008).
  • the methods can also be used to treat subjects who are immunodeficient, e.g., subjects who are infected with human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • a deficit of TH17 cells is often seen, particularly in those subjects progressing to AIDS (see, e.g., Brenchley et al, Blood, 112:2826-2835 (2008); Douek et al., Annu. Rev. Med. 60:471-84 (2009); Brenchley and Douek, Muc. Immunol. l(l):23-30 (2008); Cecchinato et al., Muc. Immunol. l(4):279-288 (2008) ).
  • the present methods are particularly useful for those subjects, as well as subjects who are immunodeficient for other reasons, e.g., subjects who are malnourished, are elderly or very young (e.g., infants under 12 months of age) (see, e.g., Siegrist and Aspinall, Nat. Rev. Immunol. 9: 185-194 (2009)), or are undergoing chemotherapy that results in immune suppression.
  • Some subjects who are immunodeficient due to a genetic mutation e.g., autosomal dominant hyper-IgE syndrome (HIES, 'Job's syndrome'), which is associated with a mutation in STAT3 (see, e.g., Milner et al., Nature
  • the methods can include administering a population of T H 17 cells obtained in vitro using a method described herein.
  • the methods described herein can be used to treat subjects with cancer, e.g., with carcinoma (defined as cancer that begins in the skin or in tissues that line or cover internal organs); sarcoma (defined as cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue); leukemia (defined as cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced and enter the blood); lymphoma and myeloma (defined as cancers that begin in the cells of the immune system); or central nervous system cancers (defined as cancers that begin in the tissues of the brain and spinal cord).
  • carcinoma defined as cancer that begins in the skin or in tissues that line or cover internal organs
  • sarcoma defined as cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue
  • leukemia defined as cancer that starts in blood-
  • the methods described herein can be used to treat subjects suffering from one or more of the following: malignant tumors of the nasal cavity, nasal sinuses, nasopharynx, larynx, trachea, bronchi, lungs, jawbones, skin, ear, bones, thyroid gland, prostate gland, ovaries, the Bartholin gland, vulva, vagina, uterine tubes, uterine body, womb, cervical, breast, urinary bladder, kidneys, gall bladder, rectum, colon, appendix, small intestine, stomach, esophagus, or sialadens.
  • diseases or disorders caused by an absent or insufficient immune response can be treated by increasing the number of T H 17 cells and/or the activity of T H 17 cells in a subject using a therapeutically effective amount of one or more AHR ligands that reduce expression of Foxp3 (e.g., 6-formylindolo[3,2- b]carbazole (FICZ) or beta-naphthoflavone (bNF), and compounds with the same effect on AHR signaling as FICZ or bNF), that are capable of promoting an increase in the number or activity of T H 17 cells in vitro and/or in vivo.
  • AHR ligands that reduce expression of Foxp3 (e.g., 6-formylindolo[3,2- b]carbazole (FICZ) or beta-naphthoflavone (bNF)
  • FICZ 6-formylindolo[3,2- b]carbazole
  • bNF beta-naphthoflavone
  • a subject in need of treatment can be administered a pharmaceutically effective dose of one or more AHR ligands that reduce expression of Foxp3 (e.g., FICZ or bNF) capable of promoting an increase in the number or activity of T H 17 cells in vitro and/or in vivo.
  • AHR ligands that reduce expression of Foxp3 (e.g., FICZ or bNF) capable of promoting an increase in the number or activity of T H 17 cells in vitro and/or in vivo.
  • a population of cells capable of differentiation into T H 17 cells can be contacted in vitro with an AHR ligand (e.g., FICZ or bNF, or a compound with the same effect on AHR signaling as FICZ or bNF), thereby effectively promoting an increase in the number of T H 17 cells in the population.
  • an AHR ligand e.g., FICZ or bNF, or a compound with the same effect on AHR signaling as FICZ or bNF
  • a population of cells containing T H 17 cells e.g., isolated T H 17 cells (e.g., 100%) or a population of cells containing at least 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% T H 17 cells
  • FICZ or bNF a compound with the same effect on AHR signaling as FICZ or bNF, thereby effectively promoting an increase in the activity of the T H 17 cells in the population.
  • the AHR ligand e.g., FICZ or bNF
  • AHR ligand e.g., FICZ or bNF
  • One or more cells from these populations can then be administered to the subject alone or in combination with one or more AHR ligands capable of promoting an increase in the number or activity of TH 17 cells in vitro and/or in vivo (e.g., FICZ or bNF, or a compound with the same effect on AHR signaling as FICZ or bNF).
  • a subject can be assessed at one or more time points, for example, using methods known in the art for assessing severity of the disease or its symptoms, to determine the effectiveness of the treatment.
  • levels of T cells producing IL- 17 TH 17
  • Treatment can then be continued without modification, modified to improve the progress or outcome (e.g., increase dosage levels, frequency of administration, the amount of the pharmaceutical composition, and/or change the mode of administration), or stopped.
  • a number of methods of evaluation of efficacy can be used, e.g., detection of levels of (ROR ⁇ t), a transcription factor associated with TH17 cell differentiation, e.g., using RT-PCR or intracellular staining/FACS analysis (see, e.g., Ivanov et al, Nat. Immunol, 8:345-50, 2007); alternatively or in addition, levels of IL- 17, IL-21, or IL- 22 can also be evaluated, e.g., using intracellular cytokine staining, ELISA, ELISPOT, or RT-PCR assays as known in the art. Clinical parameters, e.g., tumor size or growth, infection control or levels of a pathogen present (also known as "load”), can also be evaluated.
  • a therapeutically effective amount of one or more of the compositions described herein can be administered by standard methods, for example, by one or more routes of administration, e.g., by one or more of the routes of administration currently approved by the United States Food and Drug Administration (FDA; see, for example world wide web address fda.gov/cder/dsm/DRG/drg00301.htm), e.g., orally, topically, mucosally, intravenously or intramuscularly.
  • FDA United States Food and Drug Administration
  • one or more of the ligands described herein can be administered orally with surprising effectiveness.
  • compositions comprising nanoparticles linked to AHR ligands (e.g. FICZ or bNF) are surprisingly effective in delivering the ligand, both orally and by injection, and in inducing the Treg response in living animals.
  • AHR ligands e.g. FICZ or bNF
  • compositions comprising AHR ligands linked to biocompatible nanoparticles, optionally with antibodies that target the nanoparticles to selected cells or tissues.
  • the nanoparticles useful in the methods and compositions described herein are made of materials that are (i) biocompatible, i.e., do not cause a significant adverse reaction in a living animal when used in pharmaceutically relevant amounts; (ii) feature functional groups to which the binding moiety can be covalently attached, (iii) exhibit low non-specific binding of interactive moieties to the nanoparticle, and (iv) are stable in solution, i.e., the nanoparticles do not precipitate.
  • the nanoparticles can be monodisperse (a single crystal of a material, e.g., a metal, per nanoparticle) or polydisperse (a plurality of crystals, e.g., 2, 3, or 4, per nanoparticle).
  • biocompatible nanoparticles are known in the art, e.g., organic or inorganic nanoparticles. Liposomes, dendrimers, carbon nanomaterials and polymeric micelles are examples of organic nanoparticles. Quantum dots can also be used.
  • Inorganic nanoparticles include metallic nanoparticle, e.g., Au, Ni, Pt and TiO2 nanoparticles. Magnetic nanoparticles can also be used, e.g., spherical nanocrystals of 10-20 nm with a Fe 2+ and/or Fe 3+ core surrounded by dextran or PEG molecules.
  • colloidal gold nanoparticles are used, e.g., as described in Qian et al, Nat.
  • the nanoparticles are attached (linked) to the AHR ligands described herein via a functional groups.
  • the nanoparticles are associated with a polymer that includes the functional groups, and also serves to keep the metal oxides dispersed from each other.
  • the polymer can be a synthetic polymer, such as, but not limited to, polyethylene glycol or silane, natural polymers, or derivatives of either synthetic or natural polymers or a combination of these.
  • Useful polymers are hydrophilic.
  • the polymer "coating” is not a continuous film around the magnetic metal oxide, but is a "mesh” or “cloud” of extended polymer chains attached to and surrounding the metal oxide.
  • the polymer can comprise polysaccharides and derivatives, including dextran, pullanan, carboxydextran, carboxmethyl dextran, and/or reduced carboxymethyl dextran.
  • the metal oxide can be a collection of one or more crystals that contact each other, or that are individually entrapped or surrounded by the polymer.
  • the nanoparticles are associated with non-polymeric functional group compositions.
  • Methods are known to synthesize stabilized, functionalized nanoparticles without associated polymers, which are also within the scope of this invention. Such methods are described, for example, in Halbreich et al., Biochimie, 80 (5-6):379-90, 1998.
  • the nanoparticles have an overall size of less than about 1-100 nm, e.g., about 25-75 nm, e.g., about 40-60 nm, or about 50-60 nm in diameter.
  • the polymer component in some embodiments can be in the form of a coating, e.g., about 5 to 20 nm thick or more.
  • the overall size of the nanoparticles is about 15 to 200 nm, e.g., about 20 to 100 nm, about 40 to 60 nm; or about 60 nm.
  • the nanoparticles can be prepared, but in all methods, the result must be a nanoparticle with functional groups that can be used to link the nanoparticle to the binding moiety.
  • AHR ligands can be linked to the metal oxide through covalent attachment to a functionalized polymer or to non-polymeric surface- functionalized metal oxides.
  • the nanoparticles can be synthesized according to a version of the method of Albrecht et al., Biochimie, 80(5-6): 379-90, 1998.
  • Dimercapto-succinic acid is coupled to the nanoparticle and provides a carboxyl functional group.
  • functionalized is meant the presence of amino or carboxyl or other reactive groups that can be used to attach desired moieties to the nanoparticles, e.g., the AHR ligands described herein or antibodies.
  • the AHR ligands are attached to the nanoparticles via a functionalized polymer associated with the nanoparticle.
  • the polymer is hydrophilic.
  • the conjugates are made using oligonucleotides that have terminal amino, sulfhydryl, or phosphate groups, and superparamagnetic iron oxide nanoparticles bearing amino or carboxy groups on a hydrophilic polymer.
  • Carboxy functionalized nanoparticles can be made, for example, according to the method of Gorman (see WO 00/61191). Carboxy-functionalized nanoparticles can also be made from polysaccharide coated nanoparticles by reaction with bromo or chloroacetic acid in strong base to attach carboxyl groups. In addition, carboxy- functionalized particles can be made from amino-functionalized nanoparticles by converting amino to carboxy groups by the use of reagents such as succinic anhydride or maleic anhydride.
  • Nanoparticle size can be controlled by adjusting reaction conditions, for example, by varying temperature as described in U.S. Patent No. 5,262,176. Uniform particle size materials can also be made by fractionating the particles using centrifugation, ultrafiltration, or gel filtration, as described, for example in U.S. Patent No. 5,492,814.
  • Nanoparticles can also be treated with periodate to form aldehyde groups.
  • the aldehyde-containing nanoparticles can then be reacted with a diamine (e.g., ethylene diamine or hexanediamine), which will form a Schiff base, followed by reduction with sodium borohydride or sodium cyanoborohydride.
  • a diamine e.g., ethylene diamine or hexanediamine
  • Dextran-coated nanoparticles can also be made and cross-linked, e.g., with epichlorohydrin.
  • the addition of ammonia will react with epoxy groups to generate amine groups, see Hogemann et al., Bioconjug. Chem. 2000. 11(6):941-6, and Josephson et al., Bioconjug. Chem., 1999, 10(2): 186-91.
  • Carboxy-functionalized nanoparticles can be converted to amino- functionalized magnetic particles by the use of water-soluble carbodiimides and diamines such as ethylene diamine or hexane diamine.
  • Avidin or streptavidin can be attached to nanoparticles for use with a biotinylated binding moiety, such as an oligonucleotide or polypeptide. See e.g.,
  • biotin can be attached to a nanoparticle for use with an avidin-labeled binding moiety.
  • low molecular weight compounds can be separated from the nanoparticles by ultra-filtration, dialysis, magnetic separation, or other means.
  • the unreacted AHR ligands can be separated from the ligand-nanoparticle conjugates, e.g., by size exclusion chromatography.
  • colloidal gold nanoparticles are made using methods known in the art, e.g., as described in Qian et al, Nat. Biotechnol. 26(l):83-90 (2008); U.S. Pat. Nos. 7060121; 7232474; and U.S. RG. Pub. No. 2008/0166706.
  • the nanoparticles are pegylated, e.g., as described in U.S. Pat. Nos. 7291598; 5145684; 6270806; 7348030, and others.
  • compositions described herein also include antibodies to selectively target a cell; in some embodiments, the antibodies are bound to nanoparticles, e.g., the same or different nanoparticles as the AHR ligand.
  • antibody refers to full-length, two-chain immunoglobulin molecules and antigen-binding portions and fragments thereof, including synthetic variants.
  • a typical full-length antibody includes two heavy (H) chain variable regions (abbreviated herein as VH), and two light (L) chain variable regions (abbreviated herein as VL).
  • antigen-binding fragment of an antibody, as used herein, refers to one or more fragments of a full-length antibody that retain the ability to specifically bind to a target.
  • antigen-binding fragments include, but are not limited to: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHl domains; (ii) a F(ab') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHl domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., Nature 341:544-546 (1989)), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR).
  • CDR complementarity determining region
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. Science 242:423-426 (1988); and Huston et al. Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988)).
  • scFv single chain Fv
  • Such single chain antibodies are also encompassed within the term "antigen-binding fragment.”
  • T cells T cells
  • B cells dendritic cells, and/or macrophages
  • antibodies selective for one or more of those cell types can be used.
  • T cells anti- CXCR4, anti-CD28, anti-CD8, anti-TTLA4, or anti-CD3 antibodies
  • B cells antibodies to CD20, CD 19, or to B-cell receptors can be used
  • dendritic cell targeting exemplary antibodies to CDl Ic, DEC205, MHC class I or class II, CD80, or CD86 can be used
  • macrophages exemplary antiboduies to CDl Ib, MHC class I or class II, CD80, or CD86 can be used.
  • Other suitable antibodies are known in the art.
  • the methods include co-administering a specific antigen, to induce an antigen- specific response.
  • a specific antigen e.g., to induce an antigen- specific response.
  • one or more tumor-specific antigens can be administered, e.g., antigens associated with the type of tumor the subject has.
  • the specific antigens can be purified, e.g., isolated and purified polypeptides or glycopeptides, e.g., native or recombinant, and can include antigenic fragments as well.
  • the antigen is from a tumor cell, bacteria, fungus, or protozoa, i.e., a cell-associated antigen, whole cells or fragments thereof can also be administered.
  • any antigen that has been identified as potentially useful as a vaccine can be used.
  • the methods can include administering the AHR ligand, or T H 17 cells prepared by a method described herein, as part of a vaccination protocol, e.g., as an adjuvant to boost the immune response to the vaccine antigen.
  • the present methods can be incorporated into any known vaccination protocol, for administration as an adjuvant.
  • TAAs tumor-associated antigens
  • TAAs include the following: alphafetoprotein (AFP), for germ cell tumors; carcinoembryonic antigen (CEA), for cancers of the gastrointestinal tract; CA-125, for ovarian cancer; MUC-I, for breast cancer; epithelial tumor antigen (ETA), for breast cancer; tyrosinase, for malignant melanoma; melanoma-associated antigen (MAGE), for malignant melanoma; prostatic acid phosphatase or prostate specific antigen (PSA), for prostate cancer; or Melan-A/MART-1, for malignant melanoma.
  • AFP alphafetoprotein
  • CEA carcinoembryonic antigen
  • CA-125 for ovarian cancer
  • MUC-I for breast cancer
  • ETA epithelial tumor antigen
  • MAGE melanoma-associated antigen
  • PSA prostate specific antigen
  • PSA prostate specific antigen
  • ras abnormal products of ras, or p53
  • hormones e.g., ACTH, calcitonin, and human chorionic gonadotropin (HCG)
  • HCG human chorionic gonadotropin
  • Exemplary pathogen-associated antigens include antigenic polysaccharides which could be given (conjugated to protein carrier) together with FICZ, to protect children and elders against the causative agents of diseases, e.g., meningitis, e.g., linked to a peptide carrier, see, e.g., Amir-Kroll et al, J. Immunol. 170:6165-6171 (2003).
  • Exemplary polysaccharides include the surface polysaccharides Streptococcal pneumoniae; Neisseria meningitides; and Haemophilus Influenza Type b (Hib).
  • exemplary antigens include Bordatella pertussis formalin-inactivated pertussis toxins, e.g., after removal of cells from culture (acellular pertussis, aP); Clostridium tetani formalin-inactivated toxin; Corynebacterium diphtheriae formalin- inactivated toxins; Hepatitis B virus antigen (HBsAg); and various inactivated viruses/bacteria.
  • aP acellular pertussis
  • Clostridium tetani formalin-inactivated toxin e.g., after removal of cells from culture (acellular pertussis, aP
  • Clostridium tetani formalin-inactivated toxin e.g., after removal of cells from culture (acellular pertussis, aP
  • Clostridium tetani formalin-inactivated toxin e.g., after removal of cells from culture (acellular pertussis, a
  • compositions described herein that include as an active (therapeutic) agent an AHR ligand, e.g., FICZ or bNF, either alone or bound to a nanoparticle
  • pharmaceutical compositions suitable for administration to a subject e.g., a human.
  • Such compositions typically include the composition and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances are known.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, CREMOPHOR ELTM (polyethoxylated castor oil; BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the composition (e.g., an agent described herein) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, PRIMOGELTM (sodium carboxymethyl starch), or corn starch; a lubricant such as magnesium stearate or STEROTESTM; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, PRIMOGELTM (sodium carboxymethyl starch), or corn starch
  • a lubricant such as magnesium stearate or
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • Nucleic acid molecules can be inserted into vectors and used as gene therapy vectors.
  • Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see U.S. Patent 5,328,470) or by stereotactic injection (see e.g., Chen et al, PNAS 91 :3054-3057, 1994).
  • the pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can include a slow release matrix in which the gene delivery vehicle is imbedded.
  • the pharmaceutical preparation can include one or more cells which produce the gene delivery system.
  • the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. In one aspect, the pharmaceutical compositions can be included as a part of a kit.
  • the dosage used to administer a pharmaceutical compositions facilitates an intended purpose for prophylaxis and/or treatment without undesirable side effects, such as toxicity, irritation or allergic response.
  • side effects such as toxicity, irritation or allergic response.
  • human doses can readily be extrapolated from animal studies (Katocs et al., Chapter 27 In: “Remington's Pharmaceutical Sciences", 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990).
  • the dosage required to provide an effective amount of a formulation will vary depending on several factors, including the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy, if required, and the nature and scope of the desired effect(s) (Nies et al., Chapter 3, In: Goodman & Gilman's "The Pharmacological Basis of Therapeutics", 9th Ed., Hardman et al., eds., McGraw- Hill, New York, N.Y., 1996).
  • kits comprise one or more doses of a composition described herein.
  • the composition, shape, and type of dosage form for the induction regimen and maintenance regimen may vary depending on a subjects requirements.
  • dosage form may be a parenteral dosage form, an oral dosage form, a delayed or controlled release dosage form, a topical, and a mucosal dosage form, including any combination thereof.
  • a kit can contain one or more of the following in a package or container: (1) one or more doses of a composition described herein; (2) one or more pharmaceutically acceptable adjuvants or excipients (e.g., a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, and clathrate); (3) one or more vehicles for administration of the dose; (5) instructions for administration.
  • a pharmaceutically acceptable adjuvants or excipients e.g., a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, and clathrate
  • vehicles for administration e.g., a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, and clathrate
  • instructions for administration e.g., a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, and clathrate
  • Embodiments in which two or more, including all, of the components (l)-(5), are found in the same container can also be used.
  • the different components of the compositions included can be packaged in separate containers and admixed immediately before use. Such packaging of the components separately can permit long term storage without loosing the active components' functions.
  • the bioactive agents may be (1) packaged separately and admixed separately with appropriate (similar of different, but compatible) adjuvants or excipients immediately before use, (2) packaged together and admixed together immediately before use, or (3) packaged separately and admixed together immediately before use. If the chosen compounds will remain stable after admixing, the compounds may be admixed at a time before use other than immediately before use, including, for example, minutes, hours, days, months, years, and at the time of manufacture.
  • compositions included in particular kits of the present invention can be supplied in containers of any sort such that the life of the different components are optimally preserved and are not adsorbed or altered by the materials of the container.
  • Suitable materials for these containers may include, for example, glass, organic polymers (e.g., polycarbonate and polystyrene), ceramic, metal (e.g., aluminum), an alloy, or any other material typically employed to hold similar reagents.
  • Exemplary containers may include, without limitation, test tubes, vials, flasks, bottles, syringes, and the like.
  • kits can also be supplied with instructional materials. These instructions may be printed and/or may be supplied, without limitation, as an electronic-readable medium, such as a floppy disc, a CD-ROM, a DVD, a Zip disc, a video cassette, an audiotape, and a flash memory device. Alternatively, instructions may be published on a internet web site or may be distributed to the user as an electronic mail.
  • an electronic-readable medium such as a floppy disc, a CD-ROM, a DVD, a Zip disc, a video cassette, an audiotape, and a flash memory device.
  • instructions may be published on a internet web site or may be distributed to the user as an electronic mail.
  • UVB catalyzes the formation of the AHR ligand FICZ in vitro, and is thought to generate FICZ in the skin (Fritsche et al., Proc. Natl. Acad. Sci. U.S.A., 104:8851-8856, 2007).
  • AHR expression is highly up-regulated in T H 17 T cells induced in vitro by activation with TGF ⁇ l and IL-6. Moreover, AHR expression was also up-regulated when T H 17 differentiation was driven by TGF ⁇ l, IL-6 and IL-23, or when IL-21 was used instead of IL-6 (see Fig. ID).
  • mice were treated with PBS (control) or ITE, immunized with MOG35_55 peptide in CFA and monitored for EAE development.
  • Athymic nude mice are often used in cancer research because they do not reject tumor cells, from mice or other species.
  • AFP is an accepted tumor marker of HCC.
  • Figures 3 A and 3B As measured by AFP levels at seven (Fig. 3A) and 14 (Fig. 3B) days after treatment initiation, FICZ significantly suppresses tumor growth.
  • a combination treatment comprising administering FICZ with HBsAG provided somewhat better results than FICZ alone, which indicates that the co-administration of a tumor associated antigen has a synergistic effect.
  • the immune system in teleosts like the zebrafish resembles in several aspects the mammalian immune system. Macrophages, T cells, B cells have been described in teleosts (Langenau and Zon, Nat Rev Immunol.
  • zFoxp3 was over- expressed or alternatively knocked out in zebrafish developing embryos.
  • zFoxp3 was cloned from cDNA prepared from zebrafish kidney by using a TOPO® PCR cloning kit (Invitrogen, CA, USA) according to the manufacturer's instructions.
  • Zebrafish eggs were collected within 1 hr of spawning, and purified plasmids or morpholino antisense oligonucleotides were microinjected with a fine glass needle connected to an automatic injector.
  • a morpholino oligonucleotide designed to block the translation of zFoxp3 (5'-GTGTTCCAGTAGCATTAAGAAGCAT-S ') and a 5 bases mismatch control oligonucleotide (5 '-GTcTTCgAGTAcCATTAAcAAGgAT- 3') were designed and synthesized by Gene Tools (Philomath, OR). Each morpholino nucleotide was injected into the yolk of embryos at one to four cell stages.
  • Microinjection with zFoxp3 -expression constructs resulted in an up-regulation of zFoxp3 levels, concomitant with the down-regulation of IL- 17 levels.
  • microinjection with morpholino oligonucleotides designed to block the translation of zFoxp3 led to the upregulation of IL- 17 expression, which was not observed upon the injection of 5 bases mismatch negative control morpholino ( Figure 4D).
  • zFoxp3 is the functional zebrafish homologue of Foxp3 in mammals. Increases in zFoxp3 result in an increase in Treg, while a decrease in Foxp3 expression results in an increase in levels of IL- 17.
  • Gold colloid has been in use for over 50 years in the treatment of rheumatoid arthritis, these gold colloid nanoparticles have been shown to have little to no long-term toxicity or adverse effects (Paciotti et al., Drug Deliv. 11, 169 (May-Jun, 2004)). Due to their small size (10-lOOnm diameter), gold colloid nanoparticles have large surface areas on which multiple small proteins or other molecules can be conjugated (Paciotti et al., Drug Deliv. 11, 169 (May-Jun, 2004)). The PEGylation of gold colloid nanoparticles greatly enhances the overall stability of the molecule to which it is covalently bonded (Qian et al., Nat Biotechnol. 26, 83
  • EAE was induced on na ⁇ ve C57BL/6 mice and treated them, starting at day 0, weekly with 45 femtomoles of nanoparticles.
  • treatment with TCDD resulted in a complete suppression of EAE, while the AHR ligand FICZ worsened the disease ( Figure 7).
  • Weekly administration of ITE-loaded nanoparticles resulted in a significant inhibition of EAE development (Figure 7).
  • Example 5 An AHR reporter system for Identification of Modulators of AHR
  • a construct coding for Foxp3 fused to Renilla luciferase (Ren) was created to provide a simple assay to identify compounds that increase expression of AHR (and thus increase luciferase expression and fluorescence as compared to a control) or that decrease expression of AHR (and thus decrease luciferase expression and fluorescence as compared to a control).
  • HEK 293 cells were transfected as described (Bettelli et al., Proc Natl Acad Sci U S A 102, 5138-5143 (2005)) with the AHR reporter luciferase construct and a TK-Renilla Luciferase construct for normalization purposes. The cells were incubated with different concentrations of the AHR ligand
  • T cells were differentiated into Th 17 cells by in vitro activation with antibodies to CD3 and CD28 in the presence of TGF -beta and IL-21 as described

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Abstract

La présente invention concerne des méthodes destinées à augmenter la génération de cellules productrices d’IL-17 (TH17) in vivo et in vitro, et des populations enrichies de cellules TH17 pour le traitement de maladies tirant profit d’une réponse immunitaire induite ou améliorée, par exemple l’infection et le cancer.
PCT/US2009/037696 2008-03-21 2009-03-19 Modulation de la réponse immunitaire Ceased WO2009117597A1 (fr)

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AU2009225541A AU2009225541A1 (en) 2008-03-21 2009-03-19 Modulation of the immune response
CA2755933A CA2755933A1 (fr) 2008-03-21 2009-03-19 Modulation de la reponse immunitaire
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AU2019225251A1 (en) 2018-02-26 2020-10-15 AnTolRx, Inc. Tolerogenic liposomes and methods of use thereof
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11253589B2 (en) 2007-11-20 2022-02-22 The Brigham And Women's Hospital, Inc. Modulation of the immune response
CN102573470A (zh) * 2009-11-02 2012-07-11 宋嘉盛 用于介入治疗和根除癌症的ite
EP2496081A4 (fr) * 2009-11-02 2013-05-01 Jiasheng Song Ite pour intervention chirurgicale et éradication d'un cancer
EP3689347A1 (fr) * 2009-11-02 2020-08-05 Ariagen, Inc. Ite pour l'intervention et l'éradication de cancer
US10822587B2 (en) 2013-02-27 2020-11-03 The Broad Institute, Inc. T cell balance gene expression, compositions of matters and methods of use thereof
US11547698B2 (en) 2016-12-26 2023-01-10 Ariagen, Inc. Aryl hydrocarbon receptor modulators
US11427576B2 (en) 2017-11-20 2022-08-30 Ariagen, Inc. Indole compounds and their use
US11459322B2 (en) 2017-11-20 2022-10-04 Ariagen, Inc. Indole compounds and their use
US11891386B2 (en) 2017-11-20 2024-02-06 Ariagen, Inc. Indole compounds and their use
US11390621B2 (en) 2019-04-15 2022-07-19 Ariagen, Inc. Chiral indole compounds and their use

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